Our research program is devoted to the study of normal and abnormal emotions with a strong emphasis on fear and anxiety. This research is conducted using psychophysiological, psychopharmacological, and brain imaging techniques. The major areas of investigation include: 1) development of human models of fear and anxiety; 2) research on the relationship between associative learning and emotional reactivity to aversive stimuli; 3) studies of personality and temperamental dimensions of psychopathology; 4) investigations of the effects of psychotropic medications on fear and anxiety in healthy individuals and in clinical groups; 5) identification of the early manifestations of psychiatric illnesses using family studies. Although the experimental approach is restricted to humans, this program of research is strongly influenced by theories and methods from animal analogues of emotion, motivation, and associative learning. Thus, the research relies on efforts to translate findings from animal research into human experimentation and studies of psychopathology. This report focuses on three main areas of interest: 1. Studies of explicit cue fear and contextual fear as models for phasic fear and generalized anxiety, respectively 2. Psychopharmacologic investigations 3. Development of experimental models of human fear and anxiety states 4. High-risk studies 1. Explicit cued fear and contextual anxiety This series of projects focuses on anxiety, as opposed to fear. Fear is associated with a clearly identifiable, imminent threat, whereas anxiety is a generalized fear without object, an apprehensive anticipation of future potential threats. Our working hypothesis is that fear and anxiety can be modeled by cued fear and contextual fear, respectively. The distinction between cued fear and contextual anxiety was first made in fear conditioning studies in animals. Cued fear is elicited by an explicit stimulus (e.g., a light) that predicts a noxious stimulus (e.g., a shock). Contextual fear is caused by the experimental context (i.e., the cage, the experimental room) where an aversive experiment took place. We showed that a similar distinction could be made in human studies (Grillon & Davis, 1997). Several features make contextual fear an appealing model of anxiety (Grillon 2002, in press). Given the potential relevance of contextual fear for our understanding of anxiety disorders and the paucity of human research in this area, we are pursuing several areas of investigations focusing on contextual fear. The first one examines factors that are involved in the modulation of contextual fear. We have developed a protocol to assess the role of predictability on contextual fear using instructed fear procedures. Results showed that contextual fear is increased by unpredictability as long as the aversive event is sufficiently unpleasant. We are currently following-up on these findings in three areas. One investigates brain mechanisms mediating cued fear to signaled shocks and contextual anxiety to unpredictable shock in an fMRI study. Preliminary findings indicate reduced activation in medial prefrontal structures during unpredictable shocks. A second investigation assesses the effects of psychopharmacological agents. A third area explores the relevance of these findings to psychopathology by investigating contextual fear in individuals diagnosed with an anxiety disorder or selected for low or high trait anxiety. Prliminary evidence shows that high trait anxious subjects and patients with anxiety disorders show increased contextual fear. Another factor that affects contextual fear is fear conditioning. Fear conditioning is adaptive because it makes aversive events predictable. We recently reported that cued fear learning deficits were associated with increased contextual fear (Grillon, 2002), suggesting that symptoms of generalized anxiety may be secondary to basic associative learning impairments. Two ffeatures emerged in subjects showing poor cued fear conditioning: 1) high trait anxiety and 2) elevated physiological arousal at the time of testing. These results emphasize the role of attentional factors in the formation of conditioned responses, the subsequent learning of emotional responses, and the development of anxiety. 2. Psychopharmacologic investigations Our study relies on the startle reflex to measure fear and anxiety. Startle is potentiated by fear in both humans and animals. In rodents, this so-called 'fear-potentiated startle reflex' effect is reduced by drugs that reduce human anxiety such as the benzodiazepines. However, human studies with benzodiazepines have been contradictory. While two studies reported that benzodiazepines reduced fear-potentiated startle, we have been unable to confirm this effect in a study that included four experiments (Baas et al. 2002). We recently pointed out issues in psychopharmacology studies with the startle reflex (Grillon and Baas, 2002). One issue is the difficulty in separating the anxiolytic from the sedative effects of benzodiazepines. Another issue is that benzodiazepines have been tested on cued fear models, while contextual fear models may be more relevant (Grillon, 2002). We are currently testing the effect of alprazolam on cued fear and contextual fear. Benadryl is used as a non-anxiolytic sedative control drug. Results show that the benzodiazepine alprazolam reduced contextual fear but not cued fear. The inability to extinguish intense fear memories is a significant clinical problem. Finding procedures or treatments that facilitate extinction of fear memories is of paramount importance. We are currently examining whether D-cycloserine, a partial agonist at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor, facilitates extinction. The rationale for this study is that if NMDA receptor antagonists block the acquisition of fear conditioning and of extinction, it is possible that NMDA receptor agonists facilitate this type of learning. Facilitation of extinction would be therapeutically useful. Recently, D-cycloserine was found to produce a dose-dependent facilitation of extinction of conditioned fear in the rat, when assessed with fear-potentiated startle. Our study examines whether the clinically important process of extinction can also be enhanced by D-cycloserine in humans. 3. Development of experimental models of human fear and anxiety states One important aspect of our program of research is to develop procedures to study fear and anxiety in humans. Despite important recent progress, we have become increasingly dissatisfied with traditional fear conditioning protocols. There are two main issues. Conditioned responses are weak (i.e., they extinguished rapidly) and they are not well retained over time. In addition, the stimuli used in these studies are somewhat unsophisticated (e.g., geometric shapes presented on a monitor). These problems limit the development of meaningful fear conditioning procedures, more particularly for psychopharmacology and contextual fear studies. We have embarked on a project that uses computer-generated virtual reality to investigate fear conditioning and have recently documented for the first time context conditioning in virtual environment (Baas et al 2004).4. High-risk studies We are involved in two studies examining risk factors for psychiatric disorders. One study is the continuation of a NIDA grant that was given to the present PI when he was at Yale University. The investigation looks at two different familial pathways to drug addiction, antisocial personality and anxiety. The second project is a collaborative study with Dr. Myrna Weissman (Columbia University) examining psychophysiological risk-factors for depression in children and grand-children of individuals with major depression.